Inoculation of young horses with bovine papillomavirus type 1 virions leads to early infection of PBMCs prior to pseudo-sarcoid formation.
Abstract: Bovine papillomavirus types 1 and 2 (BPV-1 and BPV-2) are known to induce common equine skin tumours, termed sarcoids. Recently, it was demonstrated that vaccination with BPV-1 virus-like particles (VLPs) is safe and highly immunogenic in horses. To establish a BPV-1 challenge model for evaluation of the protective potential of BPV-1 VLPs, four foals were injected intradermally with infectious BPV-1 virions and with viral genome-based and control inocula, and monitored daily for tumour development. Blood was taken before inoculation and at weekly intervals. BPV-1-specific serum antibodies were detected by a pseudo-virion neutralization assay. Total nucleic acids extracted from tumours, intact skin and PBMCs were tested for the presence of BPV-1 DNA and mRNA using PCR and RT-PCR, respectively. Intralesional E5 oncoprotein expression was determined by immunofluorescence. Pseudo-sarcoids developed exclusively at sites inoculated with virions. Tumours became palpable 11-32 days after virion challenge, reached a size of ≤20 mm in diameter and then resolved in ≤6 months. No neutralizing anti-BPV-1 serum antibodies were detectable pre- or post-challenge. BPV-1 DNA was present in lesions but not in intact skin. In PBMCs, viral DNA was already detectable before lesions were first palpable, in concentrations correlating directly with tumour growth kinetics. PBMCs from two of two foals also harboured E5 mRNA. Immunofluorescence revealed the presence of the E5 protein in tumour fibroblasts, but not in the apparently normal epidermis overlying the lesions. Together with previous findings obtained in horses and cows, these data suggest that papillomavirus infection may include a viraemic phase.
Publication Date: 2011-06-29 PubMed ID: 21715602PubMed Central: PMC5034893DOI: 10.1099/vir.0.033670-0Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
This research investigates how inoculating young horses with bovine papillomavirus type 1 (BPV-1) leads to initial infection of Peripheral Blood Mononuclear Cells (PBMCs) before the formation of tumor-like growths called pseudo-sarcoids. The study was conducted in order to establish a challenge model for evaluating the effectiveness of a potential BPV-1 vaccine.
Research Methodology
- Four young horses were intradermally injected with infectious BPV-1 particles, along with viral genome-based and control inocula.
- The horses were monitored daily for tumor development. Blood samples were taken before inoculation and on a weekly basis afterward.
- The presence of BPV-1 antibodies was identified through a pseudo-virion neutralization assay.
- To determine the presence of BPV-1 DNA and mRNA, Polymerase Chain Reaction (PCR) and Reverse Transcription Polymerase Chain Reaction (RT-PCR) were utilized respectively on nucleic acids extracted from tumors, intact skin, and PBMCs.
- The level of E5 oncoprotein expression, a key indicator of BPV-1 infection, within the potential tumors was identified using immunofluorescence.
Major Findings
- Pseudo-sarcoids, or tumor-like growths, appeared only at sites where the BPV-1 viral particles were inoculated. The growths were palpable within 11-32 days post-inoculation, reaching up to 20mm in diameter before resolving within 6 months.
- No neutralizing BPV-1 antibodies were detectable either pre or post-inoculation, suggesting that immunogenic response to the virus might not occur.
- While BPV-1 DNA was found within the tumors, it was not detected in intact skin. Interestingly, viral DNA was detectable in PBMCs before the tumors became palpable, indicating that initial infection occurs in these cells.
- The presence of E5 oncoprotein was found in the fibroblasts of the tumors but not in the normal skin layers covering the tumors. This validates that the E5 oncoprotein is expressed in response to BPV-1 infection.
- The studies suggest a possibility of a viremia phase (presence of viruses in the bloodstream) as part of the papillomavirus infection.
Conclusion
This research shed light on the infection pathway of BPV-1 and its relation with the development of skin tumors in horses. The results could pave the way for further studies on the BPV-1 vaccination efficacy to protect horses from pseudo-sarcoid formation.
Cite This Article
APA
Hartl B, Hainisch EK, Shafti-Keramat S, Kirnbauer R, Corteggio A, Borzacchiello G, Tober R, Kainzbauer C, Pratscher B, Brandt S.
(2011).
Inoculation of young horses with bovine papillomavirus type 1 virions leads to early infection of PBMCs prior to pseudo-sarcoid formation.
J Gen Virol, 92(Pt 10), 2437-2445.
https://doi.org/10.1099/vir.0.033670-0 Publication
Researcher Affiliations
- Division of Large Animal Surgery and Orthopaedics, Equine Clinic, Veterinary University Vienna, Vienna, Austria.
- Division of Large Animal Internal Medicine, Equine Clinic, Veterinary University Vienna, Vienna, Austria.
- Division of Large Animal Surgery and Orthopaedics, Equine Clinic, Veterinary University Vienna, Vienna, Austria.
- Laboratory of Viral Oncology, Division of Immunology, Allergy and Infectious Disease, Department of Dermatology, Medical University Vienna, Vienna, Austria.
- Laboratory of Viral Oncology, Division of Immunology, Allergy and Infectious Disease, Department of Dermatology, Medical University Vienna, Vienna, Austria.
- Department of Pathology and Animal Health, Faculty of Veterinary Medicine, University of Naples Federico II, Naples, Italy.
- Department of Pathology and Animal Health, Faculty of Veterinary Medicine, University of Naples Federico II, Naples, Italy.
- Department of Hygiene, Microbiology and Social Medicine, Division of Virology, Medical University Innsbruck, Innsbruck, Austria.
- Division of Large Animal Surgery and Orthopaedics, Equine Clinic, Veterinary University Vienna, Vienna, Austria.
- Division of Large Animal Internal Medicine, Equine Clinic, Veterinary University Vienna, Vienna, Austria.
- Division of Large Animal Surgery and Orthopaedics, Equine Clinic, Veterinary University Vienna, Vienna, Austria.
- Division of Large Animal Internal Medicine, Equine Clinic, Veterinary University Vienna, Vienna, Austria.
- Division of Large Animal Surgery and Orthopaedics, Equine Clinic, Veterinary University Vienna, Vienna, Austria.
- Division of Large Animal Internal Medicine, Equine Clinic, Veterinary University Vienna, Vienna, Austria.
MeSH Terms
- Animals
- Antibodies, Viral / blood
- Bovine papillomavirus 1 / pathogenicity
- DNA, Viral / genetics
- DNA, Viral / isolation & purification
- Disease Models, Animal
- Fluorescent Antibody Technique, Direct
- Horses
- Leukocytes, Mononuclear / virology
- Neutralization Tests
- Oncogene Proteins, Viral / biosynthesis
- Oncogene Proteins, Viral / genetics
- RNA, Messenger / genetics
- RNA, Messenger / isolation & purification
- Reverse Transcriptase Polymerase Chain Reaction
- Sarcoidosis / pathology
- Sarcoidosis / virology
- Skin / pathology
- Skin / virology
Grant Funding
- P 18990 / Austrian Science Fund FWF
References
This article includes 52 references
- Amtmann E, Müller H, Sauer G. Equine connective tissue tumors contain unintegrated bovine papilloma virus DNA.. J Virol 1980 Sep;35(3):962-4.
- Bogaert L, Martens A, De Baere C, Gasthuys F. Detection of bovine papillomavirus DNA on the normal skin and in the habitual surroundings of horses with and without equine sarcoids.. Res Vet Sci 2005 Dec;79(3):253-8.
- Bogaert L, Martens A, Kast WM, Van Marck E, De Cock H. Bovine papillomavirus DNA can be detected in keratinocytes of equine sarcoid tumors.. Vet Microbiol 2010 Dec 15;146(3-4):269-75.
- Borzacchiello G, Roperto F, Campo MS, Venuti A. 1st International Workshop on Papillomavirus E5 Oncogene-a report.. Virology 2010 Dec 20;408(2):135-7.
- Brandt S, Haralambus R, Shafti-Keramat S, Steinborn R, Stanek C, Kirnbauer R. A subset of equine sarcoids harbours BPV-1 DNA in a complex with L1 major capsid protein.. Virology 2008 Jun 5;375(2):433-41.
- Brandt S, Haralambus R, Schoster A, Kirnbauer R, Stanek C. Peripheral blood mononuclear cells represent a reservoir of bovine papillomavirus DNA in sarcoid-affected equines.. J Gen Virol 2008 Jun;89(Pt 6):1390-1395.
- Brandt S, Apprich V, Hackl V, Tober R, Danzer M, Kainzbauer C, Gabriel C, Stanek C, Kofler J. Prevalence of bovine papillomavirus and Treponema DNA in bovine digital dermatitis lesions.. Vet Microbiol 2011 Mar 24;148(2-4):161-7.
- Brandt S, Schoster A, Tober R, Kainzbauer C, Burgstaller JP, Haralambus R, Steinborn R, Hinterhofer C, Stanek C. Consistent detection of bovine papillomavirus in lesions, intact skin and peripheral blood mononuclear cells of horses affected by hoof canker.. Equine Vet J 2011 Mar;43(2):202-9.
- Brandt S, Tober R, Corteggio A, Burger S, Sabitzer S, Walter I, Kainzbauer C, Steinborn R, Nasir L, Borzacchiello G. BPV-1 infection is not confined to the dermis but also involves the epidermis of equine sarcoids.. Vet Microbiol 2011 May 12;150(1-2):35-40.
- Breitburd F, Kirnbauer R, Hubbert NL, Nonnenmacher B, Trin-Dinh-Desmarquet C, Orth G, Schiller JT, Lowy DR. Immunization with viruslike particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection.. J Virol 1995 Jun;69(6):3959-63.
- Campo MS. Introduction. In: Campo MS, editor. Papillomavirus Research: From Natural History to Vaccines and Beyond. Norfolk, UK: Caister Academic Press; 2006a. pp. 1–2.
- Campo MS. Bovine papillomavirus: old system, new lessons?. In: Campo MS, editor. Papillomavirus Research: From Natural History to Vaccines and Beyond. Norfolk, UK: Caister Academic Press; 2006b. pp. 373–387.
- Chambers G, Ellsmore VA, O'Brien PM, Reid SWJ, Love S, Campo MS, Nasir L. Association of bovine papillomavirus with the equine sarcoid.. J Gen Virol 2003 May;84(Pt 5):1055-1062.
- Chow LT, Broker TR. Mechanisms and regulation of papillomavirus DNA replication. In: Campo MS, editor. Papillomavirus Research: From Natural History to Vaccines and Beyond. Norfolk, UK: Caister Academic Press; 2006. pp. 53–71.
- Coleman N, Birley HD, Renton AM, Hanna NF, Ryait BK, Byrne M, Taylor-Robinson D, Stanley MA. Immunological events in regressing genital warts.. Am J Clin Pathol 1994 Dec;102(6):768-74.
- Day PM, Lowy DR, Schiller JT. Papillomaviruses infect cells via a clathrin-dependent pathway.. Virology 2003 Mar 1;307(1):1-11.
- de Freitas AC, de Carvalho C, Brunner O, Birgel EH, Jr, Melville Paiva Dellalibera AM, Benesi FJ, Gregory L, Beçak W, de Cassia Stocco dos Santos R. Viral DNA sequences in peripheral blood and vertical transmission of the virus: a discussion about BPV-1. Braz J Microbiol 2003;34:76–78.
- Giroglou T, Florin L, Schäfer F, Streeck RE, Sapp M. Human papillomavirus infection requires cell surface heparan sulfate.. J Virol 2001 Feb;75(3):1565-70.
- Hainisch EK, Brandt S, Shafti-Keramat S, Van den Hoven R, Kirnbauer R. Safety and immunogenicity of BPV-1 L1 virus-like particles in a dose-escalation vaccination trial in horses.. Equine Vet J 2012 Jan;44(1):107-11.
- Joyce JG, Tung JS, Przysiecki CT, Cook JC, Lehman ED, Sands JA, Jansen KU, Keller PM. The L1 major capsid protein of human papillomavirus type 11 recombinant virus-like particles interacts with heparin and cell-surface glycosaminoglycans on human keratinocytes.. J Biol Chem 1999 Feb 26;274(9):5810-22.
- Kirnbauer R. Papillomavirus-like particles for serology and vaccine development.. Intervirology 1996;39(1-2):54-61.
- Kirnbauer R, Chandrachud LM, O'Neil BW, Wagner ER, Grindlay GJ, Armstrong A, McGarvie GM, Schiller JT, Lowy DR, Campo MS. Virus-like particles of bovine papillomavirus type 4 in prophylactic and therapeutic immunization.. Virology 1996 May 1;219(1):37-44.
- Knottenbelt DC. A suggested clinical classification for the equine sarcoid. Clin Tech Equine Pract 2005;4:278–295.
- Knowles G, O'Neil BW, Campo MS. Phenotypical characterization of lymphocytes infiltrating regressing papillomas.. J Virol 1996 Dec;70(12):8451-8.
- Kohrgruber N, Gröger M, Meraner P, Kriehuber E, Petzelbauer P, Brandt S, Stingl G, Rot A, Maurer D. Plasmacytoid dendritic cell recruitment by immobilized CXCR3 ligands.. J Immunol 2004 Dec 1;173(11):6592-602.
- Lancaster WD. Apparent lack of integration of bovine papillomavirus DNA in virus-induced equine and bovine tumor cells and virus-transformed mouse cells.. Virology 1981 Jan 30;108(2):251-5.
- Lancaster WD, Olson C, Meinke W. Bovine papilloma virus: presence of virus-specific DNA sequences in naturally occurring equine tumors.. Proc Natl Acad Sci U S A 1977 Feb;74(2):524-8.
- Marais HJ, Nel P, Bertschinger HJ, Schoeman JP, Zimmerman D. Prevalence and body distribution of sarcoids in South African Cape mountain zebra (Equus zebra zebra).. J S Afr Vet Assoc 2007 Sep;78(3):145-8.
- Marchetti B, Gault EA, Cortese MS, Yuan Z, Ellis SA, Nasir L, Campo MS. Bovine papillomavirus type 1 oncoprotein E5 inhibits equine MHC class I and interacts with equine MHC I heavy chain.. J Gen Virol 2009 Dec;90(Pt 12):2865-2870.
- Nasir L, Campo MS. Bovine papillomaviruses: their role in the aetiology of cutaneous tumours of bovids and equids.. Vet Dermatol 2008 Oct;19(5):243-54.
- Nasir L, Reid SW. Bovine papillomaviral gene expression in equine sarcoid tumours.. Virus Res 1999 Jun;61(2):171-5.
- Nasir L, Reid SWJ. Bovine papillomaviruses and equine sarcoids. In: Campo MS, editor. Papillomavirus Research: From Natural History to Vaccines and Beyond. Norfolk, UK: Caister Academic Press; 2006. pp. 389–397.
- OLSON C Jr, COOK RH. Cutaneous sarcoma-like lesions of the horse caused by the agent of bovine papilloma.. Proc Soc Exp Biol Med 1951 Jun;77(2):281-4.
- Pastrana DV, Buck CB, Pang YY, Thompson CD, Castle PE, FitzGerald PC, Krüger Kjaer S, Lowy DR, Schiller JT. Reactivity of human sera in a sensitive, high-throughput pseudovirus-based papillomavirus neutralization assay for HPV16 and HPV18.. Virology 2004 Apr 10;321(2):205-16.
- Ragland WL, Spencer GR. Attempts to relate bovine papilloma virus to the cause of equine sarcoid: equidae inoculated intradermally with bovine papilloma virus.. Am J Vet Res 1969 May;30(5):743-52.
- Roden RB, Kirnbauer R, Jenson AB, Lowy DR, Schiller JT. Interaction of papillomaviruses with the cell surface.. J Virol 1994 Nov;68(11):7260-6.
- Roden RB, Greenstone HL, Kirnbauer R, Booy FP, Jessie J, Lowy DR, Schiller JT. In vitro generation and type-specific neutralization of a human papillomavirus type 16 virion pseudotype.. J Virol 1996 Sep;70(9):5875-83.
- Roperto S, Brun R, Paolini F, Urraro C, Russo V, Borzacchiello G, Pagnini U, Raso C, Rizzo C, Roperto F, Venuti A. Detection of bovine papillomavirus type 2 in the peripheral blood of cattle with urinary bladder tumours: possible biological role.. J Gen Virol 2008 Dec;89(Pt 12):3027-3033.
- Roperto S, Comazzi S, Ciusani E, Paolini F, Borzacchiello G, Esposito I, Lucà R, Russo V, Urraro C, Venuti A, Roperto F. PBMCs are additional sites of productive infection of bovine papillomavirus type 2.. J Gen Virol 2011 Aug;92(Pt 8):1787-1794.
- Schiller JT. Papillomavirus vaccines. In: Garcia R, DiMaio D, editors. The Papillomaviruses. New York: Springer; 2007. pp. 337–369.
- Schiller JT, Day PM, Kines RC. Current understanding of the mechanism of HPV infection.. Gynecol Oncol 2010 Jun;118(1 Suppl):S12-7.
- . Sarcoid. In: Scott DW, Miller WH., Jr . Equine Dermatology. St Louis, Missouri, USA: Elsevier Science; 2003. pp. 719–731.
- Shafti-Keramat S, Handisurya A, Kriehuber E, Meneguzzi G, Slupetzky K, Kirnbauer R. Different heparan sulfate proteoglycans serve as cellular receptors for human papillomaviruses.. J Virol 2003 Dec;77(24):13125-35.
- Shafti-Keramat S, Schellenbacher C, Handisurya A, Christensen N, Reininger B, Brandt S, Kirnbauer R. Bovine papillomavirus type 1 (BPV1) and BPV2 are closely related serotypes.. Virology 2009 Oct 10;393(1):1-6.
- Smith JL, Campos SK, Ozbun MA. Human papillomavirus type 31 uses a caveolin 1- and dynamin 2-mediated entry pathway for infection of human keratinocytes.. J Virol 2007 Sep;81(18):9922-31.
- Spoden G, Freitag K, Husmann M, Boller K, Sapp M, Lambert C, Florin L. Clathrin- and caveolin-independent entry of human papillomavirus type 16--involvement of tetraspanin-enriched microdomains (TEMs).. PLoS One 2008 Oct 2;3(10):e3313.
- Stocco dos Santos RC, Lindsey CJ, Ferraz OP, Pinto JR, Mirandola RS, Benesi FJ, Birgel EH, Pereira CA, Beçak W. Bovine papillomavirus transmission and chromosomal aberrations: an experimental model.. J Gen Virol 1998 Sep;79 ( Pt 9):2127-35.
- Suzich JA, Ghim SJ, Palmer-Hill FJ, White WI, Tamura JK, Bell JA, Newsome JA, Jenson AB, Schlegel R. Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas.. Proc Natl Acad Sci U S A 1995 Dec 5;92(25):11553-7.
- Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, Wheeler CM, Koutsky LA, Malm C, Lehtinen M, Skjeldestad FE, Olsson SE, Steinwall M, Brown DR, Kurman RJ, Ronnett BM, Stoler MH, Ferenczy A, Harper DM, Tamms GM, Yu J, Lupinacci L, Railkar R, Taddeo FJ, Jansen KU, Esser MT, Sings HL, Saah AJ, Barr E. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial.. Lancet Oncol 2005 May;6(5):271-8.
- Voss JL. Transmission of equine sarcoid.. Am J Vet Res 1969 Feb;30(2):183-91.
- Yuan Z, Philbey AW, Gault EA, Campo MS, Nasir L. Detection of bovine papillomavirus type 1 genomes and viral gene expression in equine inflammatory skin conditions.. Virus Res 2007 Mar;124(1-2):245-9.
- Zinkernagel RM. On natural and artificial vaccinations.. Annu Rev Immunol 2003;21:515-46.
Citations
This article has been cited 12 times.- Maggi R, De Paolis L, De Santis D, Vellone VG, De Ciucis CG, Fruscione F, Mazzocco K, Ghelardi A, Marruchella G, Razzuoli E. Bovine Papillomavirus Type 1 Infection in an Equine Congenital Papilloma. Pathogens 2023 Aug 18;12(8).
- Jindra C, Hainisch EK, Brandt S. Immunotherapy of Equine Sarcoids-From Early Approaches to Innovative Vaccines. Vaccines (Basel) 2023 Mar 30;11(4).
- Hainisch EK, Jindra C, Kirnbauer R, Brandt S. Papillomavirus-like Particles in Equine Medicine. Viruses 2023 Jan 25;15(2).
- Jindra C, Hainisch EK, Rümmele A, Wolschek M, Muster T, Brandt S. Influenza virus vector iNS1 expressing bovine papillomavirus 1 (BPV1) antigens efficiently induces tumour regression in equine sarcoid patients. PLoS One 2021;16(11):e0260155.
- Pietersen I, van Zyl A, Rybicki E, Hitzeroth I. Novel Production of Bovine Papillomavirus Pseudovirions in Tobacco Plants. Pathogens 2020 Nov 28;9(12).
- Araldi RP, Assaf SMR, Carvalho RF, Carvalho MACR, Souza JM, Magnelli RF, Módolo DG, Roperto FP, Stocco RC, Beçak W. Papillomaviruses: a systematic review. Genet Mol Biol 2017 Jan-Mar;40(1):1-21.
- Mosseri S, Hetzel U, Hahn S, Michaloupoulou E, Sallabank HC, Knottenbelt DC, Kipar A. Equine sarcoid: In situ demonstration of matrix metalloproteinase expression. Vet J 2014 Nov;202(2):279-85.
- Trewby H, Ayele G, Borzacchiello G, Brandt S, Campo MS, Del Fava C, Marais J, Leonardi L, Vanselow B, Biek R, Nasir L. Analysis of the long control region of bovine papillomavirus type 1 associated with sarcoids in equine hosts indicates multiple cross-species transmission events and phylogeographical structure. J Gen Virol 2014 Dec;95(Pt 12):2748-2756.
- Foresta C, Bertoldo A, Garolla A, Pizzol D, Mason S, Lenzi A, De Toni L. Human papillomavirus proteins are found in peripheral blood and semen Cd20+ and Cd56+ cells during HPV-16 semen infection. BMC Infect Dis 2013 Dec 16;13:593.
- Araldi RP, Melo TC, Diniz N, Mazzuchelli-de-Souza J, Carvalho RF, Beçak W, Stocco RC. Bovine papillomavirus clastogenic effect analyzed in comet assay. Biomed Res Int 2013;2013:630683.
- Roperto S, Borzacchiello G, Esposito I, Riccardi M, Urraro C, Lucà R, Corteggio A, Tatè R, Cermola M, Paciello O, Roperto F. Productive infection of bovine papillomavirus type 2 in the placenta of pregnant cows affected with urinary bladder tumors. PLoS One 2012;7(3):e33569.
- Mashin VV, Sergeev AN, Martynova NN, Sergeev AA, Lys'ko KA, Raikov AO, Kataeva VV, Zagidullin NV. Viral Safety Issues in the Production and Manufacturing of Human Immunoglobulin Preparations from Equine Plasma/Serum. Pharm Chem J 2022;56(4):532-537.
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists